Rapidly disintegrable solid preparation

ABSTRACT

A rapidly disintegrable solid preparation which comprises (i) a pharmacologically active ingredient, (ii) a sugar and (iii) a low-substituted hydroxypropylcellulose having 5 % by weight or more to less than 7 % by weight of hydroxypropoxyl group. The rapidly disintegrable solid preparation has fast disintegrability, suitable strength and no roughness.

This application is a continuation of U.S. application Ser. No.11/403,799, filed Apr. 13, 2006, which is a continuation of 09/800,839,filed Mar. 7, 2001, which is a division of 09/403,429, filed Oct.20,1999, which is the national stage filing of International PatentApplication No.: PCT/JP99/04015 filed Jul. 27, 1999.

TECHNICAL FIELD

The present invention relates to a solid preparation having fastdisintegrability in the oral cavity with the existence of saliva, in alittle water, or in the stomach particularly a rapidly disintegrablesolid preparation which is useful as an orally disintegrable solidpreparation.

BACKGROUND ART

It has been desired to develop an orally disintegrable solid preparationwhich can be easily administered to elders or children without water. Asbackground arts which disclose such a preparation, for example, thereare the following background arts.

JP-A-9-48726 discloses an orally rapidly disintegrable preparationproduced by wetting in a moldable way on humidifying. It comprises adrug and a material which can retain the shape after molding and drying.As such materials, a sugar, sugar alcohol and a water-soluble polymermaterial are exemplified.

JP-A-9-71523 discloses a tablet containing a drug, crystallinecellulose, a low-substituted hydroxypropylcellulose and a lubricant. Ithas fast disintegrability in the oral cavity.

EP-A 839526 discloses a solid pharmaceutical preparation containing apharmacologically active ingredient, erythritol, crystalline celluloseand a disintegrator.

However, these background arts have not described (i) apharmacologically active ingredient, (ii) a sugar and (iii) alow-substituted hydroxypropylcellulose having 5% by weight or more toless than 7% by weight of hydroxypropoxyl group of the presentinvention.

DISCLOSURE OF INVENTION

There has been desired the development of a rapidly disintegrable solidpreparation having fast disintegrability in the existence of saliva inthe oral cavity, in a little water or in the stomach, having suitablestrength (hardness) so that it may not be damaged through productionprocesses and distribution, and further having no roughness.

The present invention relates to:

(1) a rapidly disintegrable solid preparation which comprises (i) apharmacologically active ingredient, (ii) a sugar and (iii) alow-substituted hydroxypropylcellulose having 5% by weight or more toless than 7% by weight of hydroxypropoxyl group;

(2) the preparation of the above (1), which is an orally rapidlydisintegrable solid preparation;

(3) the preparation of the above (1) or (2), which is a tablet;

(4) the preparation of the above (1), wherein the sugar is a sugaralcohol;

(5) the preparation of the above (4), wherein the sugar alcohol ismannitol or erythritol;

(6) the preparation of the above (1), wherein the sugar is comprised inan amount of 5 to 97 parts by weight per 100 parts by weight of thesolid preparation;

(7) the preparation of the above (1), wherein the low-substitutedhydroxypropylcellulose having 5% by weight or more to less than 7% byweight of hydroxypropoxyl group is used in an amount of 3 to 50 parts byweight per 100 parts by weight of the solid preparation;

(8) the preparation of the above (1), wherein the pharmacologicallyactive ingredient is lansoprazole;

(9) the preparation of the above (1), wherein the pharmacologicallyactive ingredient is voglibose;

(10) the preparation of the above (1), wherein the pharmacologicallyactive ingredient is manidipine hydrochloride;

(11) the preparation of the above (1), wherein the pharmacologicallyactive ingredient is pioglitazone hydrochloride; (12) the preparation ofthe above (1), wherein the pharmacologically active ingredient iscandesartan cilexetil;

(13) the preparation of the above (3) which comprises fine granules;

(14) the preparation of the above (13), wherein the pharmacologicallyactive ingredient is comprised in the fine granules. (15) thepreparation of the above (14), wherein (i) a sugar and (ii) alow-substituted hydroxypropylcellulose having 5% by weight or more toless than 7% by weight of hydroxypropoxyl group are comprised in thesolid preparation separately from the fine granules;

(16) the preparation of the above (15), wherein the sugar is in anamount of 5 to 97 parts by weight per 100 parts by weight of the rest ofthe solid preparation other than the fine granules;

(17) the preparation of the above (15), wherein the low-substitutedhydroxypropylcellulose having 5% by weight or more to less than 7% byweight of. hydroxypropoxyl group is in an amount of 3 to 50 parts byweight per 100 parts by weight of the rest of the solid preparationother than the fine granules;

(18) use of a low-substituted hydroxypropylcellulose having 5% by weightor more to less than 7% by weight of hydroxypropoxyl group for producinga rapidly disintegrable solid preparation comprising a pharmacologicallyactive ingredient and a sugar; and

(19) a method for improving fast disintegrability of a solid preparationcomprising a pharmacologically active ingredient and a sugar, which ischaracterized in that a low-substituted hydroxypropylcellulose having 5%by weight or more to less than 7% by weight of hydroxypropoxyl group iscontained therein.

1) Pharmacologically Active Ingredient

The pharmacologically active ingredients used in the present inventionare in any condition such as solid, powdery, crystalline, oily andsolution conditions. As such pharmacologically active ingredients, forexample, one or more ingredient(s) selected from the group comprisingnourishing and cordial agents, antipyretic-anodyne-anti-inflammatorydrugs, psychotropics, antianxiety drugs, antidepressants,hypnotic-sedative drugs, spasmolytics, central nervous system drugs,brain metabolism ameliorating agents, brain circulation amelioratingagents, antiepileptics, sympathomimetics, gastrointestinal agents,antacids, antiulcer agents, antitussive-expetorants, antiemetics,respiratory accelerators, bronchodilators, antiallergic drugs, dentalbuccal drugs, antihistamines, cardiotonics, antiarrythmic drugs,diuretics, antihypertensive agents, vasoconstrictors, coronaryvasodilators, peripheral vasodilators, antihypolipidemic agents,cholagogues, antibiotics, chemotherapeutic drugs, antidiabetic agents,drugs for osteoporosis, antirheumatism agents, skeletal musclerelaxants, antivertigos, hormones, alkaloid narcotics, sulfa drugs,arthrifuges, blood coagulation inhibitors, antitumor agents, drugs forAlzheimer's disease and the like are exemplified.

As the nourishing and cordial agents, for instance, vitamins such asvitamin A, vitamin D, vitamin E (such as d-α-tocopherol acetate and thelike), vitamin B, (such as dibenzoylthiamine, fursultiaminehydrochloride and the like), vitamin B₂ (such as riboflavin butyrate andthe like), vitamin B₆ (such as pyridoxine hydrochloride and the like),vitamin C (such as ascorbic acid, sodium L-ascorbate and the like) andvitamin B₁₂ (such as hydroxocobalamin acetate, cyanocobalamin and thelike); minerals such as calcium, magnesium, iron and the like; proteins,amino acids, oligosaccharides, crude drugs and the like are exemplified.

As the antipyretic-anodyne-antiinflammatory drugs, for instance,aspirin, acetaminophen, ethenzamide, ibuprofen, diphenhydraminehydrochloride, dl-chlorpheniramine maleate, dihydrocodeine phosphate,noscapine, methylephedrine hydrochloride, phenylpropanolaminehydrochloride, caffeine, anhydrous caffein, serrapeptase, lysozymechloride, tolfenamic acid, mefenamic acid, sodium diclofenac, flufenamicacid, salicylamide, aminopyrine, ketoprofen, indometacin, bucolome,pentazocine and the like are exemplified.

As the antipsychotics, for instance, chlorpromazine, reserpine and thelike are exemplified.

As the antianxiety drugs, for instance, alprazolam, chlordiazepoxide,diazepam and the like are exemplified.

As the antidepressants, for instance, imipramine, maprotilinehydrochloride, amphetamine and the like are exemplified.

As the hypnotic-sedative drugs, for instance, estazolam, nitrazepam,diazepam, perlapine, sodium phenobarbital and the like are exemplified.

As the spasmolytics, for instance, scopolamine hydrobromide,di-phenhydramine hydrochloride, papaverine hydrochloride and the likeare exemplified.

As the central nervous system drugs, for instance, citicoline and thelike are exemplified.

As the brain metabolism ameliorating agents, for instance, meclofenoxatehydrochloride and the like are exemplified.

As the brain circulation ameliorating agents, for instance, vinpocetineand the like are exemplified.

As the antiepileptics, for instance, phenytoin, carbamazepine and thelike are exemplified.

As the sympathomimetics, for instance, isoproterenol hydrochloride andthe like are exemplified.

As the gastrointestinal agents, for instance, stomachic-digestives suchas diastase, saccharated pepsin, scopolia extract, cellulase AP3, lipaseAP and cinnamon oil; agents for intestinal disorders such as berberinechloride, resistant lactic acid bacterium, Lactobacillus bifidus and thelike are exemplified.

As the antacids, for instance, magnesium carbonate, sodiumhydrogen-carbonate, magnesium aluminometasilicate, synthetichydrotalcite, precipitated calcium carbonate, magnesium oxide and thelike are exemplified.

As the antiulcer agents, for instance, lansoprazole, omeprazole,rabeprazole, pantoprazole, famotidine, cimetidine, ranitidinehydrochloride and the like are exemplified.

As the antitussive-expetorants, for instance, chloperastinehydrochloride, dextromethorphan hydrobromide, theophylline, potassiumguaiacolsulfonate, guaiafenesin, codeine phosphate and the like areexemplified.

As the antiemetics, for instance, difenidol hydrochloride,metoclopramide and the like are exemplified.

As the respiratory accelerators, for instance, levallorphan tartrate andthe like are exemplified.

As the bronchodilators, for instance, theophylline, salbutanol sulfateand the like are exemplified.

As the antiallergic drugs, for instance, amlexanox, seratrodast and thelike are exemplified.

As the dental buccal drugs, for instance, oxytetracycline, triamcinoloneacetonide, chlorhexidine hydrochloride, lidocaine and the like areexemplified.

As the antihistamines, for instance, diphenhydramine hydrochloride,prornethazine, isothipendyl hydrochloride, dl-chlorpheniramine maleateand the like are exemplified.

As the cardiotonics, for instance, caffeine, digoxin and the like areexemplified.

As the antiarrythmic drugs, for instance, procainamide hydrochloride,propranolol hydrochloride, pindolol and the like are exemplified.

As the diuretics, for instance, isosorbide, furosemide, thiazides suchas HCTZ and the like are exemplified.

As the antihypertensive agents, for instance, delapril hydrochloride,captopril, hexamethonium bromide, hydrazine hydrochloride, labetalolhydrochloride, manidipine hydrochloride, candesartan cilexetil,methyldopa, losartan, valsartan, eprosartan, irbesartan, tasosartan,telmisartan, and the like are exemplified.

As the vasoconstrictors, for instance, phenylephrine hydrochloride andthe like are exemplified.

As the coronary vasodilators, for instance, carbocromen hydrochloride,molsidomine, verapamil hydrochloride and the like are exemplified.

As the peripheral vasodilators, for instance, cinnarizine and the likeare exemplified.

As the antihypolipidemic agents, for instance, sodium cerivastatin ,simvastatin, sodium pravastatin and the like are exemplified.

As the cholagogues, for instance, dehydrocholic acid, trepibutone andthe like are exemplified.

As the antibiotics, for instance, cephems such as cefalexin, cefaclor,amoxicillin, pivmecillinam hydrochloride, cefotiam hexetylhydrochloride, cefadroxil, cefixime, cefditoren pivoxil, cefterampivoxyl, cefpodoxime proxetil, cefotiam dihydrochloride, cefozopranhydrochloride, cefmenoxime hemihydrochloride, sodium cefsulodin;synthetic antibacterial agents such as ampicillin, ciclacillin, sodiumsulbenicillin , nalidixic acid and enoxacin; monobactams such as sodiumcarumonam; penems; carbapenems and the like are exemplified.

As the chemotherapeutic drugs, for instance, sulfamethizole,sulfamethizole hydrochloride, thiazosulfone and the like areexemplified.

As the antidiabetic agents, for instance, tolbutamide, voglibose,pioglitazone hydrochloride, glibenclamide, troglitazone, rosiglitazonemaleate, acarbose, miglitol, emigitate and the like are exemplified.

As the drugs for osteoporosis, for instance, ipriflavone and the likeare exemplified.

As the skeletal muscle relaxants, for instance, methocarbamol and thelike are exemplified.

As the antivertigos, for instance, meclizine hydrochloride,dimenhydrinate and the like are exemplified.

As the antirheumatism agents, for instance, methotrexate, bucillamine,and the like are exemplified.

As the hormones, for instance, sodium liothyronine, dexamethasone sodiumphosphate, prednisolone, oxendolone, leuprorelin acetate and the likeare exemplified.

As the alkaloid narcotics, for instance, opium, morphine hydrochloride,ipecac, oxycodone hydrochloride, opium alkaloids hydrochlorides, cocainehydrochloride and the like are exemplified.

As the sulfa drugs, for instance, sulfamine, sulfisomidine,sulfamethizole and the like are exemplified.

As the arthrifuges, for instance, allopurinol, colchicine and the likeare exemplified.

As the blood coagulation inhibitors, for instance, dicoumarol and thelike are exemplified.

As the antitumor agents, for instance, 5-fluorouracil, uracil, mitomycinand the like are exemplified.

As the drugs for Alzheimer's disease, for instance, idebenone,vinpocetine and the like are exemplified.

Among the above pharmacologically active ingredients, nourishing andcordial agents, antipyretic-anodyne-antiinflammatory drugs,hypnotic-sedative drugs, central nervous system drugs, gastrointestinalagents, antiulcer agents, antitussive-expetorants, antiallergic drugs,antiarrhythmic drugs, diuretics, antihypertensive agents,vasoconstrictors, coronary vasodilators, antihypolipidemic agents,antidiabetic agents, drugs for osteoporosis, skeletal muscle relaxants,antivertigos and the like are preferably used.

In the present invention, the pharmacologically active ingredientspreferably used are antiulcer agents such as lansoprazole; antidiabeticagents such as voglibose and pioglitazone hydrochloride; andantihypertensive agents such as manidipine hydrochloride and candesartancilexetil and the like are exemplified.

Two or more pharmacologically active ingredients can be optionally usedin an admixture in a rapidly disintegrable solid preparation of thisinvention.

The pharmacologically active ingredient is optionally diluted by thediluents generally used in the fields of medical treatment and food. Inaddition, it is optionally treated for the purpose of masking thebitterness of the pharmacologically active ingredient.

The above pharmacologically active ingredient is used in an amount of,for example, 0.01 to 70 parts by weight, preferably 0.02 to 50 parts byweight, more preferably 0.05 to 30 parts by weight, per 100 parts byweight of the solid preparation.

2) Sugar

As the sugars used in the present invention, for example, sugar, starchsugar, lactose, honey and sugar alcohol are exemplified. Such sugars areoptionally used in an admixture thereof with suitable ratio.

As the sugar, for example, sucrose, coupling sugar,fructo-oligosaccharide, palatinose are exemplified.

As the starch sugar, for example, glucose, maltose, powdered sugar,starch syrup, fructose and fruit sugar and the like are exemplified.

As the lactose, for example, lactose, isomerized lactose (lactulose),reduced lactose (lactitol) and the like are exemplified.

As the honey, various kinds of honey which are generally edible areexemplified.

As the sugar alcohol, for example, sorbitol, mannitol, maltitol, reducedstarch saccharide, xylitol, reduced paratinose, erythritol, and the likeare exemplified. As erythritol is optionally one used which is producedby fermentation using glucose as a starting material with yeast ingeneral and has at most 50 mesh of the particle size. Such erythritol iscommercially available [for example, from Nikken Chemicals Co., Ltd.(Japan)].

The above sugars are preferably water-soluble sugars. The water-solublesugars mean any water-soluble sugars which need at most 30 ml of waterwhen 1 g of sugar is added into water and then dissolved within 30minutes at 20° C. by strongly shaking every 5 minutes for 30 seconds.

In the present invention, the sugar is preferably the sugar alcohol,more preferably mannitol or erythritol.

In order to obtain sufficient strength of the preparation andsufficiently fast disintegrability, the sugar is used in an amount of 5to 97 parts by weight, preferably 10 to 90 parts by weight, per 100parts by weight of the solid preparation in case of the solidpreparation not comprising fine granules. On the other hand, the sugaris used in an amount of 5 to 97 parts by weight, preferably 10 to 90parts by weight, per 100 parts by weight of the rest of the solidpreparation other than the fine granules in case of the solidpreparation comprising fine granules.

For example, mannitol or erythritol is usually used in an amount of 5 to90 weight %, preferably 10 to 80 weight %, more preferably 20 to 80weight %, especially preferably 50 to 80 weight % relative to the wholesolid preparation in case of the solid preparation not comprising finegranules. On the other hand, mannitol or erythritol is usually used inan amount of 5 to 90 weight %, preferably 10 to 80 weight %, morepreferably 20 to 80 weight %, especially preferably 50 to 80 weight %relative to the rest of the solid preparation other than the finegranules in case of the solid preparation comprising fine granules.

3) Low-Substituted Hydroxypropylcellulose Having 5% by Weight or More toLess than 7% by Weight of Hydroxypropoxyl Group (L-HPC) 3-1) Productionof L-HPC

The “low-substituted hydroxypropylcellulose having 5% by weight or moreto less than 7% by weight of hydroxypropoxyl group (hereinafter,optionally referred to L-HPC) ” used in the present invention can beproduced in accordance with well-known methods, for example, methodsdescribed in JP-B-57-53100 or its analogous methods thereof.

At first, alkaline cellulose containing free alkaline and propyleneoxide are reacted to obtain the crude low-substitutedhydroxypropylcellulose containing free alkaline.

Concretely, for example, raw material pulp such as wood pulp and cottonleader is immersed in 10 to 50% concentration of aqueous solution ofsodium hydroxide, and pressed to obtain the alkaline cellulose of whichNaOH/cellulose ratio is 0.1 to 1.2 (ratio by weight). Next, the crudelow-substituted hydroxypropylcellulose containing free alkaline isobtained by reacting the resulting alkaline cellulose and propyleneoxide with stirring at 20 to 90° C. for 2 to 8 hours. Propylene oxide isused in an amount so that the content of hydroxypropoxyl group in thedesired low-substituted hydroxypropylcellulose can be 5% or more byweight to less than 7% by weight.

The crude low-substituted hydroxypropylcellulose containing freealkaline is dispersed in water or hot water containing 5 to 80% of acidwhich is need to neutralize the all amount of alkaline, and a part ofthe crude low-substituted hydroxypropylcellulose containing freealkaline is dissolved therein. Further, acid is added to neutralize theremained alkaline.

After the neutralization, processes such as drainage, drying andgrinding are performed in accordance with the conventional method toobtain the desired low-substituted hydroxypropylcellulose.

3-2) Property of L-HPC

The particle diameter of L-HPC used in the present invention is, forexample, 5 to 60 μmas average particle diameter. Preferably, it is 10 to40 μm as average particle diameter.

In the above ranges, in case that L-HPC having relatively large particlediameter (for example, L-HPC having 26 to 40 μm of average particlediameter) is used, a pharmaceutical preparation being superior indisintegrability can be produced. On the other hand, in case that L-HPChaving relatively small particle diameter (for example, L-HPC having 10to 25 μm of average particle diameter) is used, the pharmaceuticalpreparation being superior in strength of the preparation can beproduced.

Accordingly, the particle diameter of L-HPC can be suitably selectedaccording to the character of the desired pharmaceutical preparation.

In order to obtain sufficient strength of the preparation andsufficiently fast disintegrability, the L-HPC in the present inventionis used in an amount of 3 to 50 parts by weight, preferably 5 to 40parts by weight, per 100 parts by weight of the solid preparation incase of the solid preparation not comprising fine granules. On the otherhand, the L-HPC in the present invention is used in an amount of 3 to 50parts by weight, preferably 5 to 40 parts by weight, per 100 parts byweight of the rest of the solid preparation other than the fine granulesin case of the solid preparation comprising fine granules.

As mentioned above, by using L-HPC, it becomes possible to improve fastdisintegrability, particularly the orally fast disintegrability, of thesolid preparation containing the pharmacologically active ingredient andthe sugar.

4) Dosage Forms

As the dosage form of the rapidly disintegrable solid preparation of thepresent invention, for example, tablet, granule, fine granule and thelike, preferably tablet is exemplified. Among rapidly disintegrabletablets such as an orally disintegrable tablet and a tabletdisintegrable in water, the orally disintegrable tablet is preferable.

5) Other Ingredients

Unless fast disintegrability (particularly, fast disintegrability in theoral cavity) or strength of the preparation is interfered with, therapidly disintegrable solid preparation of the present invention mayfurther contain a variety of additives which are commonly used in themanufacture of preparations in general dosage forms. Amount of suchadditives to be used is one commonly used in the manufacture ofpreparations in general dosage forms. As such additives, for example,binders, acids, foaming agents, artificial sweeteners, flavorants,lubricants, colorants, stabilizers, excipients, disintegrators and thelike are exemplified.

As the above binders, for example, hydroxypropylcellulose,hydroxypropylmethylcellulose, crystalline cellulose, pregelatinizedstarch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan andthe like are exemplified. These two or more binders can be used in anadmixture in a given ratio. The use of crystalline cellulose as thebinder provides the solid preparation which exhibits more excellentstrength of the preparation while retaining excellent fastdisintegrability in the oral cavity. As the crystalline cellulose,microcrystalline cellulose is also included. The “crystalline cellulose”includes a refined one having partially α-cellulose depolymerization. Ascrystalline cellulose, for example, CEOLUS KG 801, Avicel PH 101, AvicelPH 102, Avicel PH 301, Avicel PH 302, Avicel RC-A591 NF (crystallinecellulose·carmellose sodium), Avicel RC-591 (crystallinecellulose·carmellose sodium)and the like are concretely exemplified.Among them, CEOLUS KG 801 referred to as highly moldable crystallinecellulose is preferably used. Such crystalline celluloses are optionallyused in an admixture thereof with suitable ratio. Such crystallinecelluloses can be commercially available (manufactured by Asahi ChemicalIndustry Co., Ltd. (Japan)). The crystalline cellulose is used in anamount of, for example, 1 to 50 parts by weight, preferably 2 to 40parts by weight, more preferably 2 to 20 parts by weight, per 100 partsby weight of the solid preparation in case of the solid preparation notcomprising fine granules. Likewise, the crystalline cellulose is used inan amount of, for example, 1 to 50 parts by weight, preferably 2 to 40parts by weight, more preferably 2 to 20 parts by weight, per 100 partsby weight of the solid preparation apart from fine granules in case ofthe solid preparation comprising fine granules.

As the acids, for example, citric acid, tartaric acid, malic acid andthe like are exemplified.

As the foaming agents, for example, sodium bicarbonate and the like areexemplified.

As the artificial sweeteners, for example, saccharin sodium, dipotassiumglycyrrhizinate, aspartame, stevia, thaumatin and the like areexemplified.

As the flavorants, for example, lemon, lemon lime, orange, mentol,strawberry and the like are exemplified.

As the lubricants, for example, magnesium stearate, sucrose fatty acidester, polyethylene glycol, talc, stearic acid and the like areexemplified. Use of polyethylene glycol as the lubricant provides thestable solid preparation of which the decomposition over time of thepharmacologically active ingredient is controlled. At that time,polyethylene glycol is used in an amount of, for example, 0.01 to 10parts by weight, preferably 0.1 to 5 parts by weight, per 100 parts byweight of the solid preparation in case of the solid preparation notcomprising fine granules. Likewise, polyethylene glycol is used in anamount of, for example, 0.01 to 10 parts by weight, preferably 0.1 to 5parts by weight, per 100 parts by weight of the solid preparation apartfrom fine granules in case of the solid preparation comprising finegranules.

As the colorants, for example, various food colorants such as FoodYellow No. 5, Food Red No. 2, Food Blue No. 2 and the like; food lakes,red iron oxide and the like are exemplified.

As the stabilizers, for example, a basic substance in the case of thebasic pharmacologically active ingredient and an acidic substance in thecase of the acidic pharmacologically active ingredient are exemplified.

As the excipients, for example, lactose, sucrose, D-mannitol, starch,corn starch, crystalline cellulose, light silicic anhydride, titaniumoxide and the like are exemplified.

As the disintegrators, for example, disintegrators called superdisintegrators such as crospovidone [manufactured by ISP Inc. (U.S.A.),BASF (Germany)), croscarmellose sodium [FMC-Asahi Chemical Industry Co.,Ltd. (Japan)], carmellose calcium [Gotoku Chemical (Yakuhin), (Japan)];hydroxypropylcellulose; low-substituted hydroxypropylcellulose;carboxymethylstarch sodium [Matsutani Chemical Co., Ltd. (Japan)]; cornstarch and the like are exemplified. Among them, crospovidone ispreferably used. Such two or more disintegrators are optionally used inan admixture thereof with suitable ratio.

As crospovidone, any cross-linked homopolymer such as1-ethenyl-2-pyrrolidinone homopolymer may be used, and usuallycrospovidone having a molecular weight of at least 1,000,000 is used. Ascrospovidone which is commercially available, for example, Cross-linkedpovidone, Kollidone CL [manufactured by BASF (Germany)], PolyplasdoneXL, Polyplasdone XL-10, INF-10 [manufactured by ISP Inc., (U.S.A.)],polyvinylpolypyrrolidone, PVPP, 1-vinyl-2-pyrrolidinone homopolymer andthe like are concretely exemplified.

Two or more of these disintegrants can be as a mixture in a given ratio.For example, (i) crospovidone solely, or (ii) crospovidone and anotherdisintegrant(s) is preferably used.

Such disintegrator is used in an amount of, for example, 0.1 to 20 partsby weight, preferably 1 to 10 parts by weight, more preferably 3 to 7parts by weight, per 100 parts by weight of the solid preparation incase of the solid preparation not comprising fine granules. Likewise,such disintegrator is used in an amount of, for example, 0.1 to 20 partsby weight, preferably 1 to 10 parts by weight, more preferably 3 to 7parts by weight, per 100 parts by weight of the rest of the solidpreparation other than the fine granules in case of the solidpreparation comprising fine granules.

5-1) Other Ingredients for Dosage Forms, Especially of Acid-LabilePharmacologically Active Ingredient

In case that the pharmacologically active ingredient is an acid-labileone such as lansoprazole, omeprazole, rapeprazole, pantoprazole and thelike, a basic inorganic salt is preferably incorporated to stabilize thepharmacologically active ingredient in the solid preparation.

The “basic inorganic salt” includes, for example, a basic inorganic saltof sodium, potassium, magnesium and/or calcium, preferably a basicinorganic salt of magnesium and/or calcium. Among others, preferred is abasic inorganic salt of magnesium.

The basic inorganic salt of sodium includes, for example, sodiumcarbonate, sodium hydrogencarbonate, sodium phosphate, sodiumhydrogenphosphate and the like.

The basic inorganic salt of potassium includes, for example, potassiumcarbonate, potassium hydrogencarbonate, potassium phosphate, potassiumhydrogenphosphate, potassium sodium carbonate and the like.

The basic inorganic salt of magnesium includes, for example, heavymagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide, magnesium metasilicate aluminate, magnesium silicatealuminate, magnesium silicate, magnesium aluminate, synthetichydrotalcite [MG₆Al₂(OH)₁₆.CO₃.4H₂O], aluminum magnesium hydroxide[2.5MgO.Al₂O₃.xH₂O] and the like. Among others, preferred is heavymagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide and the like.

The basic inorganic salt of calcium includes, for example, precipitatedcalcium carbonate, calcium hydroxide, and the like.

The preferable examples of the “basic inorganic salt” are magnesiumbasic inorganic salt, and more preferable examples include heavymagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide, and the like.

Such basic inorganic salt of magnesium or calcium, and the like has abasic pH (not less than 7) when it is in the form of a 1% aqueoussolution or suspension.

Two or more of these basic inorganic salts (preferably a basic inorganicsalt of magnesium, a basic inorganic salt of calcium, and the like) canbe used as a mixture in a given ratio. The amount of the basic inorganicsalt to be used is appropriately selected depending on the kind of thebasic inorganic salt and is, for instance, 0.3 to 200 parts by weight,preferably 1 to 100 parts by weight, more preferably 10 to 50 parts byweight, especially preferably 20 to 40 parts by weight relative to thepharmacologically active ingredient.

6) Dosage Form Containing Fine Granules (e.g., Tablet)

As was mentioned before, the rapidly disintegrable preparation of thepresent invention can be used in any solid dosage form such as tablet,granule, fine granule and the like . In case that it is a tablet, thetablet can contain fine granules. The fine granules may contain thepharmacologically active ingredient. These dosage forms can be preparedby a conventional method or its analogous method.

7) Fine Granule Containing Core

The fine granule can contain a core together with or separately from thepharmacologically active ingredient. As such a core, for example, (1) aspherical granulated product comprising crystalline cellulose andlactose [e.g., a spherical granulated product being 100 to 200 μm andcomprising crystalline cellulose (3 parts) and lactose (7 parts)(Nonpareil 105 (trade name), manufactured by Freund Industrial Co., Ltd.(Japan)), a spherical granulated product being 150 to 250 μm andcomprising crystalline cellulose (3 parts) and lactose (7 parts)(Nonpareil NP-7:3 (trade name), manufactured by Freund Industrial Co.,Ltd. (Japan), a spherical granulated product being 150 to 250 μm andcomprising crystalline cellulose (5 parts) and lactose (5 parts)(Nonpareil NP-5:5 (trade name), manufactured by Freund Industrial Co.,Ltd. (Japan)) and the like], (2) a spherical granulated product being150 to 250 μm and comprising crystalline cellulose [avicel SP (tradename), manufactured by Asahi Chemical Industry Co., Ltd. (Japan) and thelike) and the like are exemplified.

In case that a core is used, the core is optionally coated with thepharmacologically active ingredient and the like, and further coated formasking taste or smell and/or for imparting enteric dissolubility orsustained-release property by well known methods. In this case, such acore forms a fine granule comprising the pharmacologically activeingredient. As a coating agent in this case, for example, enteric-coatedpolymers (e.g., cellulose acetate phthalate (CAP), methacrylatecopolymer L, methacrylate copolymer LD (Eudragit L30D-55(trade name;manufactured by Rohm GmbH (Germany))), methacrylate copolymer S,hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetatesuccinate, hydroxypropylmethylcellulose acetate succinate, KollICoatMAE30DP (trade name; manufactured by BASF (Germany)), Polyquid PA-30(trade name; manufactured by SanyoKasei (Japan)),carboxymethylethylcellulose, shellac, methacrylate copolymer [e.g.,Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D(trade name) and the like] triethyl citrate, polyethylene glycol,acetylated monoglyceride, triacetin, castor oil, and the like), gastricdissolvable polymers (e.g., polyvinylacetal diethylaminoacetate,aminoalkyl methacrylate copolymer and the like), water-soluble polymers(e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose and thelike), slightly soluble-polymers (e.g., ethylcellulose, aminoalkylmethacrylate copolymer RS, ethyl acrylate methyl methacrylate copolymerand the like), wax and the like are exemplified. One or more kind(s) ofcoating agents are used in an admixture.

7-1) Production of Fine Granules

The “fine granules” in the present invention can be produced by a knowngranulation method.

The “granulation method” includes, for example, rolling granulationmethod (e.g., centrifugal rolling granulation, etc.), fluidized-bedgranulation (e.g., rolling fluidized-bed granulation, fluidizedgranulation, etc.), stirring granulation and the like. Among others,preferred is fluidized-bed granulation method, more preferred is rollingfluidized-bed granulation method.

Concrete example of the “rolling granulation method” includes a methodusing “CF apparatus” manufactured by Freund Industrial Co., Ltd. (Japan)and the like. Concrete examples of the “rolling fluidized-bedgranulation method” include methods using “SPIR-A-FLOW”, “multi plex”manufactured by Powrex Corp. (Japan), “New-Marumerizer ” manufactured byFuji Paudal Co., Ltd. (Japan), and the like. The method for spraying themixture can be suitably selected in accordance with the kind ofgranulator, and may be, for example, any one of a top spray method, abottom spray method, a tangential spray method, and the like. Amongothers, a tangential spray method is preferred.

The “fine granules” in the present invention can be coated with anyother ingredient including the active ingredient and the others, by aconventional coating method or its analogous method. For example, amethod which comprises coating a core comprising crystalline celluloseand lactose with an acid-labile physiologically active substance isemployed in case that pharmacologically active ingredient is anacid-labile physiologically active substance.

For example, used is a method described in JP-A-5-92918 (coatingmethod), which comprises coating a core comprising crystalline celluloseand lactose with an acid-labile physiologically active substance, ifnecessary together with a basic inorganic salt, binders, lubricants,excipients, a water-soluble polymer, etc. (hereinafter, may beabbreviated to “coating layer”). For example, employed is a method whichcomprises coating a core with an acid-labile physiologically activesubstance and a basic inorganic salt, and then further with binders,lubricants, excipients, a water-soluble polymer, etc.

7-2) Property of Core for Fine Granules

The average particle diameter of the “cores” is 250 μm or less,preferably 50 to 250 μm, more preferably 100 to 250 μm, especiallypreferably 100 to 200 μm. The “cores” having the above average particlediameter include particles which all pass through a #50 sieve (300 μm),particles where 5 w/w % or less of the total remain on a #60 sieve (250μm), and particles where 10 w/w % or less of the total pass through a#282 sieve (53 μm). The specific volume of the “core” is 5 ml/g or less,preferably 3 ml/g or less.

Examples of the “core” include:

(1) a spherical granulated product comprising crystalline cellulose andlactose, (2) a spherical granulated product being 150 to 250 μm andcomprising crystalline cellulose (Avicel SP, manufactured by AsahiChemical Co., Ltd. (Japan)), (3) a stirring granulated product being 50to 250 μm and comprising lactose (9 parts) and a starch (1 part), (4) amicro particle being 250 μm or less classified as a spherical granulecomprising micro crystalline cellulose described in JP-A-61-213201, (5)a processed product such as wax formed to a sphere by spraying ormelting granulation, (6) a processed product such as gelatin beadscomprising oil component, (7) calcium silicate, (8) starch, (9) a porousparticle such as chitin, cellulose, chitosan, etc, and (10) a bulkproduct such as granulated sugar, crystalline lactose or sodiumchloride, and processed preparations thereof. Further, these cores maybe produced in accordance with per se known grinding method orgranulation method, and sifted to prepare the particles having thedesired particle diameter.

The above “spherical granulated product comprising crystalline celluloseand lactose” includes, for example (i) a spherical granulated productbeing 100 to 200 μm and comprising crystalline cellulose (3 parts) andlactose (7 parts) [e.g., Nonpareil 105 (70-140) (particle diameter of100 to 200 μm), manufactured by Freund Industrial Co., Ltd. (Japan)],(ii) a spherical granulated product being 150 to 250 μm and comprisingcrystalline cellulose (3 parts) and lactose (7 parts) [e.g., NonpareilNP-7:3, manufactured by Freund Industrial Co., Ltd. (Japan)], (iii) aspherical granulated product being 100 to 200 μm and comprisingcrystalline cellulose (4.5 parts) and lactose (5.5 parts) [e.g.,Nonpareil 105T (70-140) (particle diameter of 100 to 200 μm),manufactured by Freund Industrial Co., Ltd. (Japan)], (iv) a sphericalgranulated product being 150 to 250 μm and comprising crystallinecellulose (5 parts) and lactose (5 parts) [e.g., Nonpareil NP-5:5,manufactured by Freund Industrial Co., Ltd. (Japan)], and the like.

In order to produce a pharmaceutical preparation which is superior indissolution while retaining suitable strength, the “core” includes, forexample, preferably the spherical granulated product comprisingcrystalline cellulose and lactose, more preferably the sphericalgranulated material comprising crystalline cellulose and lactose andcontaining 50 weight % or more of lactose relative to the whole solidpreparation. Among others, preferred is a core comprising 40 to 50weight % of crystalline cellulose and 50 to 60 weight % of lactose.

As the “core” employed in the present invention, preferably, there maybe employed the spherical granulated product comprising crystallinecellulose and lactose, more preferably the spherical granulated productwith a diameter of 100 to 200 μm and comprising crystalline cellulose(4.5 parts) and lactose (5.5 parts).

The “core” may contain the physiologically active substance such as theabove described pharmacologically active ingredient. Also, the “core”may not contain the physiologically active substance because the releaseof the physiologically active substance can be controlled by a coatinglayer containing the physiologically active substance.

The “core” is preferably as uniform a sphere as possible, for reducingthe irregularity of the coating, in addition. to being a powdery core.

The ratio of the “coating layer” to the “core” can be selected withinthe range in which it is possible to control dissolution of thephysiologically active substance and particle size of the composition,for example, usually 50 to 400 parts by weight relative to 100 parts byweight of the core.

7-3) Coating Method of Fine Granules

The coating layer may be constructed by plural layers. At least onelayer of the plural layers must contain the physiologically activesubstance. The combination of various layers such as a coating layer notcontaining the active ingredient, a base coating layer, and an entericcoating layer which constitute the coating layer can be suitablyselected.

In case that the “core” is coated, for example, the abovephysiologically active substance and the water-soluble polymer can beemployed in an admixture thereof. The admixture may be a solution or adispersion, and can be prepared by using an organic solvent such aswater or ethanol or an admixture thereof.

The concentration of the water-soluble polymer in the admixture variesaccording to the ratio of the physiologically active substance and theadditives, and is usually 0.1 to 50 weight %, preferably 0.5 to 10weight % relative to the whole solid preparation, in order to retain thebinding strength of the physiologically active substance to the core andmaintain the viscosity of the mixture so as not to reduce theworkability.

Where the coating layer comprises plural layers, the concentration ofthe physiologically active substance in each layer may be changedsuccessively or gradually by selecting for the content ratio orviscosity of the water-soluble polymer or by successive coating withmixtures varying in the ratio of the physiologically active substanceand the other additives. In the above case, it may be coated with amixture in which the content ratio of the water-soluble polymer is outof the range of 0.1 to 50 weight %, as long as the coating layer as awhole contains 0.1 to 50 weight % of the water-soluble polymer. Further,in forming the inactive coat according to known methods, the coatinglayer optionally comprises some layers such that the inactive layer mayblock each layer containing the physiologically active substance.

Also, in case of two or more physiologically active substances notsuited in the compatibility, the core may be coated by employing eachmixture together or separately.

The above coated material is dried, and passed through sieves to obtaina “composition” having uniform size. Because the form of the compositionis usually according to the core, a fine granule being in the form of arough sphere can be obtained. As the sieve may be employed, for examplea #50 circular sieve (300 μm). The composition is obtained by selectingthose which pass through the #50 circular sieve.

The “fine granule” in the present invention can be produced inaccordance with in the same manner as above granulation method, forexample, a method which comprises coating the composition with anenteric coating layer, in order to protect the physiologically activesubstance or to impart enteric dissolution. If necessary, thecomposition coated with an enteric coating layer may be further coatedby a water-soluble sugar alcohol, preferably mannitol. In such case, thestrength of the orally disintegrable tablet comprising fine granules isimproved.

The “enteric coating layer” is preferably a layer having 20 to 70 μm ,preferably 30 to 50 μm of thickness and coating the whole surface of thecomposition containing the physiologically active substance.Accordingly, the smaller particle diameter of the composition, thehigher the weight % of the enteric coating layer in the whole finegranule. In the fine granule of the present invention, the “entericcoating layer” is 30 to 70 weight %, preferably 50 to 70 weight %, ofthe fine granule as a whole.

The “enteric coating layer” are optionally constructed by plural (e.g.,2 or 3) layers. For example, the used is a method which comprisescoating a composition with an enteric coating layer havingpolyethyleneglycol, and then with an enteric coating layer havingtriethyl citrate, followed by being coated with an enteric coating layerhaving polyethyleneglycol.

8) Production of Rapidly Disintegrable Solid Preparation

The rapidly disintegrable solid preparation of the present invention canbe produced in accordance with a conventional method or its analogousmethod in the field of pharmaceutical preparation. As such method, forexample, a method comprising blending the pharmacologically activeingredient, the sugar and the low-substituted hydroxypropylcellulosehaving 5% by weight or more to less than 7% by weight of hydroxypropoxylgroup after adding water if needed, molding, and then drying if neededis exemplified. However, the rapidly disintegrable solid preparation ofthe present invention can be produced also without water.

8-1) Production of Rapidly Disintegrable Tablet

For the production of the orally disintegrable tablet, a conventionalmolding method or its analogous method can be applied by usingappropriate ingredients selected from the above-mentioned ones includingthe fine granules.

Preferred example of the method for the orally disintegrable tablethaving the fine granules of the coated. cores comprises:

-   (i) coating a core comprising crystalline cellulose and lactose with    a physiologically active substance and an excipient, followed by    being coated with a coating layer comprising a water-soluble polymer    to obtain a composition,-   (ii) coating the resultant composition with an enteric coating layer    having polyethyleneglycol, and then with an enteric coating layer    having triethyl citrate, and then followed by being coated by    mannitol to obtain fine granule, and-   (iii) blending the resultant fine granule with an additive, followed    by molding.

The molding procedure can be carried out, for instance, by tablettingwith a pressure of 0.5 to 3 ton/cm², preferably 1 to 2 ton/cm² by usinga single-punch tabletting machine [Kikusui Seisakusho (Japan)] or arotary type tabletting machine [Kikusui Seisakusho (Japan)] when a solidpreparation is a tablet, especially an orally disintegrable tablet.

The drying procedure can be carried out by any techniques such as vacuumdrying, fluidized-bed drying and the like used to dry the generalpharmaceutical preparation.

The blending procedure can be carried out by any conventional blendingtechniques such as admixing, kneading, granulating and the like. Theblending procedure is carried out by using an apparatus such as VerticalGranulator VG10 [manufactured by Powrex Corp. (Japan)], UniversalKneader [manufactured by Hata Iron Works Co., Ltd. (Japan)], fluidizedbed granulator LAB-1 and FD-3S [manufactured by Powrex Corp. (Japan)],centrifugal fluidized coating granulator MP-10, MP-400 [manufactured byPowrex Corp. (Japan)] and the like.

In the present specification, “coating” means also partial coating andadhesion or adsorption in addition to coating the whole surface of anobject (e.g., core) which is to be coated.

“Spherical” means also forms having a curved surface such as formshaving elliptic cross sections, and forms in the shapes of eggplants anddrops in addition to spheres.

“Average particle diameter” means volume based distribution mediandiameter (median diameter: 50% particle diameter from cumulativedistribution), unless otherwise specified. It can be measured by, forexample, a laser diffraction particle distribution measurement method.Concretely exemplified is a method using Raiser Diffraction Analyzer,type: HEROS RODOS [trade name; manufactured by Sympatec (Germany)].

In the present invention, “fine granules” have an average particlediameter of about 400 μm or less, in order that roughness is not felt inthe mouth. Preferably, the average particle diameter of the finegranules is 300 to 400 μm.

Aside from the average particle diameter of the above “fine granules”,regarding the maximum particle size, the particle diameter issubstantially 425 μm or less, and preferably substantially 400 μm orless. Preferably, the particle diameter is substantially 300 to 425 μm,more preferably 300 to 400 μm. “Substantially” as used in the phases of“the particle diameter is substantially 425 μm or less” and “theparticle diameter is substantially 400 Aim or less” means that theparticles may include a small quantity (about 5 weight % or less) ofparticles whose particle diameter is out of the above described range,to include the inevitable contaminant particles.

The “composition” may contain water-soluble polymers, the above binders,lubricants, excipients and the like in common use as pharmaceuticalmaterials. The amount of such water-soluble polymers, binders,lubricants, and excipients is selected from amounts commonly employed inthe manufacture of preparations in general dosage forms.

The “water-soluble polymer” includes, for example, a water-solublepolymer which is soluble in ethanol (i.e., an ethanol-solublewater-soluble polymer) such as a cellulose derivative (e.g.,hydroxypropyl cellulose, which may be referred to as “HPC” hereinafter),polyvinylpyrrolidone, etc.; a water-soluble polymer which is insolublein ethanol (i.e., an ethanol-insoluble water-soluble polymer) such as acellulose derivative (e.g., hydroxypropylmethyl cellulose, which may bereferred to as “HPMC” hereinafter, methyl cellulose, carboxymethylcellulose sodium, etc.), sodium polyacrylate, polyvinyl alcohol, sodiumalginate, and guar gum, etc.

When such water-soluble polymers are used, the dissolution of drugs(physiologically active substances) can be controlled by employing themin combination with the ethanol-soluble water-soluble polymer andethanol-insoluble water-soluble polymer or by employing them incombination with some water-soluble polymers having different viscosity.

In the present invention, the “water-soluble polymer” is preferably, acellulose derivative such as HPC, HPMC, and methyl cellulose, andpolyvinyl alcohol. More preferred is a cellulose derivative such as HPC,HPMC.

The “HPC” contains, for example, about 53.4 to 77.5 weight %, morepreferably about 60 to 70 weight %, of hydroxypropoxyl group. Theviscosity of 2 weight % aqueous solution of HPC at 20° C. is usuallyabout 1 to 150,000 cps (centipoise). As the above HPC, hydroxypropylcellulose defined in Japanese Pharmacopoeia may be employed.Hereinafter, all viscosity of HPC is a value of 2 weight % aqueoussolution at 20° C.

The “HPMC” is a mixed ether which is connected by a methoxy group and ahydroxypropoxy group. The content of the methoxy group of HPMC is, forexample, about 19 to 30 weight %. The content of the hydroxypropoxygroup is, for example, about 4 to 12 weight %. The viscosity of 2 weight% aqueous solution of HPMC at 20 ° C. is usually about 1 to 40,000centistokes. As such HPMC may be employed hydroxypropylmethyl cellulose2208 defined by Japanese Pharmacopoeia, hydroxypropylmethyl cellulose2906 defined by Japanese Pharmacopoeia, hydroxypropylmethyl cellulose2910 defined by Japanese Pharmacopoeia, and so forth. Hydroxypropylcellulose(s) may be employed alone or in an admixture of two or morethereof.

The content of the water-soluble polymer such as HPC and/or HPMC isusually about 0.1 to 50 weight %, preferably about 1 to 30 weight %, asagainst the whole “composition” containing the physiologically activesubstance, in order to control the dissolution of the physiologicallyactive substance in the composition containing the physiologicallyactive substance and retain a high content of the physiologically activesubstance.

In the present invention, the “fine granules” may contain, for example,titanium oxide as a masking agent.

The diameter of the “orally disintegrable tablet” of the presentinvention is about 5 to 20 mm , preferably about 7 to 15 mm, morepreferably about 8 to 13 mm.

The “orally disintegrable tablet” optionally may not comprise lubricantinside the tablet.

When the “fine granule” of the present invention is used for a tabletexcept for an orally disintegrable tablet, the diameter of the tablet isabout 5 to 10 mm, preferably about 5 to 8 mm. When the fine granule ofthe present invention is used for a capsule, the size of the capsule ispreferably a #2 capsule or less. 9) Property of Rapidly DisintegrableSolid Preparation The rapidly disintegrable solid preparation of thepresent invention thus obtained exhibits fast disintegrability ordissolubility in the oral cavity, water or stomach, and suitablestrength of the preparation. Further the rapidly disintegrable solidpreparation of the present invention is improved in chalky taste and hasno roughness.

9-1) Disintegration Time

The orally disintegration time of the rapidly disintegrable solidpreparation of the present invention (the time for healthy male orfemale adults to complete disintegration by buccal saliva) is usually 5to 50 seconds, preferably 5 to 40 seconds, more preferably 5 to 35seconds.

The disintegration time in the stomach of the rapidly disintegrablesolid preparation of the present invention (the time for healthy male orfemale adults to complete disintegration) is shorter than that of thenormal preparation such as a normal tablet.

The disintegration time of the rapidly disintegrable solid preparationof the present invention in water is usually 5 to 40 seconds, preferably5 to 30 seconds, more preferably 5 to 25 seconds.

9-2) Strength of Preparation

The strength of the rapidly disintegrable solid preparation of thepresent invention (measurement with a tablet hardness tester) is usually2 to 20 kg, preferably 4 to 15 kg.

9-3) Administration Manner

The rapidly disintegrable solid preparation of the invention isespecially used for an orally disintegrable tablet and can beadministered without water or together with water.

As administration methods, there are listed (1) a method ofadministration by dissolution or disintegration together with a littlewater, or without water and with saliva in the oral cavity, not to beswallowed as it is, or (2) a method of administration with water, whereit is swallowed as it is. Also, the tablet may be administered dissolvedor disintegrated with water.

The “orally disintegrable tablet” of the present invention isadvantageously used in (a) cases where administration without water isnecessary, (b) cases of administration to a patients who have difficultyin swallowing tablets, or (c) cases of administration to the aged or tochildren where there is a fear of blocking the throat if it is in usualtablet form.

The rapidly disintegrable solid preparation of the present invention canbe safely administered orally to mammals such as mouse, rat, rabbit,cat, dog, bovine, horse, monkey, human and the like.

9-4) Dose and Specific Embodiments

While the dosage amount of the rapidly disintegrable solid preparationvaries depending on a pharmacologically active ingredient, a subject, akind of disease and the like, the dosage amount is selected so that thedosage amount of the pharmacologically active ingredient can be aneffective amount.

In case of the above (a), the orally disintegrable tablet is preferablyused for antipyretic agents, analgesic agents, anti-inflammatory agents,antianxiety drugs, antitussive-expectorants, anti motion sicknessagents, drugs for prevention and treatment for car-sickness, and thelike.

In case of the above (b), the orally disintegrable tablet is preferablyused for preventing and/or treating hypertension, hyperlipermia,diabetes, bronchial asthma, cerebrovascular diseases, and the like.

9-4-1) Lansoprazole

For instance, when lansoprazole is used as the pharmacologically activeingredient, the rapidly disintegrable solid preparation of the presentinvention is useful for treatment and prevention of digestive ulcer(such as gastric ulcer, duodenal ulcer, anastomic ulcer,Zollinger-Ellison syndrome), gastritis, reflex esophagitis and the like;eradication of H. pylori; suppression of upper gastrointestinal bleedingcaused by digestive ulcer, acute stress ulcer and hemorrhagic gastritis;suppression of upper gastrointestinal bleeding caused by invasive stress(such as stress caused by a large-scale operation necessitating thefollowing intensive management or cerebrovascular disease, head injury,failure of many organs, burn injury of a wide range which necessitateintensive care); treatment and prevention of ulcer caused bynon-steroidal anti-inflammatory agent; treatment and prevention ofgastric hyperacidity and ulcer caused by postoperative stress;administration before anesthesia and the like. The dosage amount of thepreparation per an adult (body weight: 60 kg) is 0.5 to 1500 mg/day,preferably 5 to 150 mg/day, as lansoprazole.

9-4-2) Voglibose

When voglibose is used as the pharmacologically active ingredient, therapidly disintegrable solid preparation of the present invention isuseful for treatment and prevention of obesity, adiposis, lipemia,diabetes mellitus and the like. The dosage amount of the preparation peran adult (body weight: 60 kg) is 0.01 to 30 mg/day, preferably 0.1 to 3mg/day, as voglibose. The rapidly disintegrable solid preparation can beadministered once a day, or 2 to 3 times separately a day.

9-4-3) Manidipine.HCI

When manidipine hydrochloride is used as the pharmacologically activeingredient, the rapidly disintegrable solid preparation of the presentinvention is useful for treatment and prevention of circulatory systemdiseases such as hypertension, ischemic heart disease (e.g., anginapectori, myocardial infarction and the like), cerebral and peripheralcirculatory disorders (e.g., cerebral infarction, transient ischemicattack, constriction of renal artery and the like) and the like. Thedosage amount of the preparation per an adult (body weight: 60 kg) is 1to 200 mg/day, preferably 10 to 20 mg/day, as manidipine hydrochloride.The rapidly disintegrable solid preparation is usually administered oncea day after breakrapidly.

9-4-4) Pioglitazone.HCI

When pioglitazone hydrochloride is used as the pharmacologically activeingredient, the rapidly disintegrable solid preparation of the presentinvention is useful as the insulin resistance improving agent and thelike, and for treatment and prevention of diabetes mellitus. The dosageamount of the preparation per an adult (body weight: 60 kg) is 7.5 to 60mg/day, preferably 15 to 45 mg/day, as pioglitazone hydrochloride. Therapidly disintegrable solid preparation can be administered once a day,or 2 to 3 times separately a day.

9-4-5) Candesartan Cilexetil

Further, when candesartan cilexetil is used as the pharmacologicallyactive ingredient, the rapidly disintegrable solid preparation of thepresent invention is useful for treatment and prevention ofhypertension, heart diseases, cerebral apoplexy, renal diseases and thelike. The dosage amount of the preparation per an adult (body weight: 60kg) is 1 to 50 mg/day, preferably 2 to 30 mg/day, as candesartancilexetil.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is more specifically explained by means of thefollowing Reference Examples, Examples and Test Examples. It is to beunderstood that the present invention is not limited to these Examples.

Unless otherwise specifically indicated, the following “%” means % byweight.

Also, the content of hydroxypropoxyl group is measured in accordancewith the methods described in Japanese Pharmacopoeia (e.g., 13thedition). The physical properties (hardness and disintegration time) ofthe tablets were determined by the following test methods.

(1) Hardness Test

Determination was carried out with a tablet hardness tester[manufactured by Toyama Sangyo Co. Ltd. (Japan)]. The test was performedin 10 runs and mean values were shown.

(2) Oral Disintegration Time

Time for complete disintegration or dissolution of the tablets only bysaliva in the oral cavity was determined.

EXAMPLES Reference Example 1

An alkaline cellulose comprising 24.1% of NaOH, 1.7% of Na₂CO₃, 42.9% ofcellulose, 31.8% of H₂O was obtained by immersing wood pulp in 49%aqueous solution of sodium hydroxide and then by pressing it. A reactorwas charged with 100 parts by weight of the alkaline cellulose. Then,nitrogen gas replacement was carried out. After the replacement, 5 partsby weight of propylene oxide was charged in the reactor and reacted withstirring at 40° C. for 1 hour, at 50° C. for 1 hour and at 70° C. for 1hour to provide 103 parts by weight of a reactant.

On the other hand, a kneader was charged with 2.5 parts by weight of hotwater at 65° C. and 0.13 parts by weight of glacial acetic acid (40% byweight against equivalent for neutralization, initial neutralized acid)and therein, 1 part by weight of the above resulting alkaline cellulosewas dispersed. Then, the temperature was adjusted at 30° C. to dissolvea part of the reactant, and 0.20 part by weight of glacial acetic acid(remain of equivalent for neutralization, complete neutralized acid) toprovide a processed fiber product containing a part of dissolution and apart of deposit.

The resulting product was washed with hot water at 80° C., drained,dried, ground by means of high rolling impact grinder, and sifted bymeans of a 100 mesh sieve to provide the powder of low-substitutedhydroxypropylcellulose LH-33 (content of hydroxypropoxyl group: 5.8% byweight, average particle diameter: 17.8 μm).

Reference Example 2

Powders of low-substituted hydroxypropylcellulose LH-23, which have alittle bigger average particle diameter (content of hydroxypropyl group:5.7% by weight, average particle diameter: 30.8 μm) were obtained in thesame manner as in Reference

Example 1. Example 1

(1) Production of Powders Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10] was charged with 900 g of Nonpareil 105 (trade name)(particle diameter: 100 to 200 μm). While the inlet air temperature andthe outlet air temperature were controlled at 70° C. and 30° C.respectively, the Nonpareil was coated by spraying a spray liquid of thefollowing composition prepared in advance in accordance with thetangential spray method at the spray rate of 22 g/min. Then, drying wascarried out for 10 minutes. The resulting granules were sieved through a#60 circular sieve (250 μm) and a #100 circular sieve (150 μm) toprovide 2186 g of powders (150 to 250 μm) having a core.

[Spray Liquid] Lansoprazole 927 g Magnesium carbonate 309 gLow-substituted hydroxypropylcellulose LH-32 154.5 g (Content ofhydroxypropyl group: 8.8% by weight) (Average particle diameter: 17.57μm) Hydroxypropylcellulose (Type SSL) 309 g Purified water 3955 g(2) Production of film-undercoated powders having a core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10] was charged with 2040 g of the above powders having acore. While the inlet air temperature and the outlet air temperaturewere controlled at 75° C. and 40° C. respectively, an undercoatingliquid of the following composition prepared in advance was sprayed inaccordance with the tangential spray method at the spray rate of 13g/min. 2145 g of film-undercoated powders having a core was obtained.

[Undercoating Liquid] Hydroxypropylmethylcellulose 264 g (Type 2910,viscosity: 3 centistokes) Purified water 5016 g(3) Production of enteric-coated powders having a core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10] was charged with 1710 g of the above film-undercoatedpowders having a core. While the inlet air temperature and the outletair temperature were controlled at 70° C. and 40° C. respectively, anenteric film coating liquid of the following composition prepared inadvance was sprayed in accordance with the tangential spray method atthe spray rate of 19 g/min. Then, drying was carried out for 7 minutes.The resulting granules were sieved through a #42 circular sieve (355 μm)and a #80 circular sieve (177 μm) to provide 2393 g of powders (177 to355 μm) having a core. [Enteric film coating liquid] Eudragit L30D-555016.4 g Eudragit NE30D 559.0 g Triethyl citrate 333.7 g Glycerylmonostearate 106.5 g Polysorbate 80 34.8 g Red iron oxide 1.8 g Purifiedwater 2547.1 g(4) Production of mannitol-overcoated enteric-coated powders having acore

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10] was charged with 600 g of the above enteric-coatedpowders having a core. While the inlet air temperature and the outletair temperature were controlled at 65° C. and 32° C. respectively, afilm coating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at the spray rateof 11 g/min. Then, drying was carried out for 7 minutes. 617 g ofovercoated enteric-coated powders having a core was obtained. [Filmcoating liquid] Mannitol 33 g Purified water 297 g(5) Production of mannitol granulated powders

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1]was charged with 800 g of mannitol [manufactured by Merck Japan Co.,Ltd.], and granulation was carried out while spraying 315 g of purifiedwater. The granules were dried to provide 727.3 g of granulated powders.

(6) Production of mixed powders

To 105 g of the above overcoated enteric-coated powders having a corewere added 97.3 g of the above mannitol-granulated powders, 15.0 g oflow-substituted hydroxypropyl cellulose LH-33 (content ofhydroxypropoxyl group: 5.8% by weight, average particle diameter: 17.8μm), 22.5 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Industry Co., Ltd. (Japan)), 7.5 g ofcrospovidone, 1.5 g of anhydrous citric acid, 0.45 g of aspartame and0.75 g of magnesium stearate, which were admixed in a bag to give mixedpowders.

(7) Production of orally disintegrable tablets

250 g of the above mixed powder was tabletted by a pounder (15R, 11 mmin diameter) using a rotary type tabletting machine at the tablettingpressure of 1.5 ton/cm² to provide tablets each weighing 500 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 5.9 kg and 30 seconds respectively.

Example 2

(1) Production of granules having a core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 900 g of Nonpareil 105 (tradename) (particle diameter of 100 to 200 μm). With the inlet airtemperature and the temperature of the loading being controlled at 65°C. and about 30° C. respectively, the Nonpareil was coated by spraying abulk liquid of the following composition prepared in advance inaccordance with the tangential spray method at a spray rate of 22 g/min. The spraying operation was stopped when the specified amount 5661g of the bulk liquid had been sprayed, and then drying was carried outin the granulator for 8 minutes. The resulting granules were sievedthrough a #42 circular sieve (350 μm) and a #100 circular sieve (150 μm)to provide 2074 g of granules having a core.

Bulk liquid: Lansoprazole 1080 g Magnesium carbonate 360 gLow-substituted hydroxypropyl cellulose LH-32 180 g (hydroxypropoxylgroup contents: 8.8 weight %) Hydroxypropyl cellulose (Type SSL) 360 gPurified water 4680 g(2) Production of film-undercoated granules having a core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 2074 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 78° C. and about 40° C., respectively, anundercoating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 22 g /min. The spraying operation was stopped when the specifiedamount 10 1980 g of the undercoating liquid had been sprayed, and thendrying was carried out in the granulator for 9 minutes. The resultinggranules were sieved through a #42 circular sieve (350 μm) and a #100circular sieve (150 μm) to provide 2555 g of film-undercoated granuleshaving a core.

Undercoating liquid: Hydroxypropylmethylcellulose 252 g (Type 2910,viscosity: 3 centistokes) Titanium oxide (TiO₂) 108 g Sterilized Talc(trade name) 108 g [produced by Matsumura Sangyo Co. Ltd. (Japan)]Low-substituted hydroxypropyl cellulose LH-32 180 g (hydroxypropoxylgroup contents: 8.8 weight %) Mannitol 252 g Purified water 3600 g(3) Production of enteric coated granules having a core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 1320 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 80° C. and about42° C., respectively, an enteric film coating liquid (A) of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 22 g /min. The specifiedamount 1638 g of the enteric film coating liquid had been sprayed.

Enteric film coating liquid (A): Eudragit L30D-55 1219.2 g EudragitNE30D 134.4 g Polyethylene glycol 6000 40.8 g Glyceryl monostearate 24.0g Polysorbate 80 7.2 g Ferric oxide 0.24 g Ferric oxide (yellow) 0.24 gCitric acid anhydrous 0.48 g Purified water 1693 g

Following this, with the inlet air temperature and the temperature ofthe loading being controlled at 76° C. and about 42° C., respectively,an enteric film coating liquid (B) of the following composition preparedin advance was sprayed in accordance with the tangential spray method ata spray rate of 22 g /min. The specified amount 6552 g of the entericfilm coating liquid had been sprayed.

Enteric film coating liquid (B): Eudragit L30D-55 4032 g Eudragit NE30D447.8 g Triethyl citrate 269.3 g Glyceryl monostearate 86.4 gPolysorbate 80 25.9 g Ferric oxide 0.86 g Ferric oxide (yellow) 0.86 gCitric acid anhydrous 0.72 g Purified water 2624 g

Following this, with the inlet air temperature and the temperature ofthe loading being controlled at 80 ° C. and about 42 ° C., respectively,an enteric film coating liquid (A) of the above mentioned compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 22 g /min. The specified amount 819 g of theenteric film coating liquid had been sprayed.

(4) Production of enteric coated and mannitol coated granules having acore Following (3), with the inlet air temperature and the temperatureof the loading being controlled at 85° C. and about 35° C.,respectively, an film coating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 22 g /min. using a centrifugal fluidizedcoating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type2)]. The spraying operation was stopped when the specified amount 882 gof the film coating liquid had been sprayed, and then drying was carriedout in the granulator for 10 minutes. The resulting granules were sievedthrough a #35 circular sieve (420 μm) and a #60 circular sieve (250 μm)to provide 1964 g of enteric coated and mannitol coated granules havinga core.

The average particle diameter of the obtained granules was 333.7 μm.

Film coating liquid: Mannitol 180 g Purified water 1080 g(5) Production of mixed powders

To 270 g of the above enteric coated and mannitol coated granules havinga core were added 204.0 g of mannitol, 30 g of low-substitutedhydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone,3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesiumstearate and 3 g of flavor [STRAWBERRY DURAROME (trade name),manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed ina bag to give mixed powders.

(6) Production of orally disintegrable tablets 570 g of the above mixedpowders were tabletted using Autograph (trade name; compressing forcemeasurement apparatus) with a punch having a beveled edge, 13 mm indiameter, at a tabletting pressure of 1.5 ton/cm², to provide tabletseach weighing 570 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 2.6 kg and 20 seconds, respectively.

The acid-resistance of the obtained tablet was 3.5%.

Example 3

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1]was charged with 0.6 g of voglibose, 410.4 g of erythritol [manufacturedby Nikken Chemicals Co., Ltd. (Japan)], 120.0 g of low-substitutedhydroxypropylcellulose LH-33 (content of hydroxypropoxyl group: 5.8 Soby weight, average particle diameter: 17.8 μm), 30.0 g of CEOLUS KG-801[manufactured by Asahi Chemical Industry Co., Ltd. (Japan)], 30 g ofcrospovidone, 6.0 g of anhydrous citric acid and 1.2 g of aspartame, andgranulation was carried out while spraying purified water. After drying,1.8 g of magnesium stearate was incorporated. The resulting powder wastabletted by a pounder (beveled edge, 10 mm in diameter) using a rotarytype tabletting machine at the tabletting pressure of 1.0 ton/cm² toprovide tablets each weighing 300 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 10.7 kg and 26 seconds respectively.

Example 4

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1]was charged with 0.6 g of voglibose, 440.4 g of erythritol [manufacturedby Nikken Chemicals Co., Ltd. (Japan)], 120.0 g of low-substitutedhydroxypropylcellulose LH-33 (content of hydroxypropoxyl group: 5.8% byweight, average particle diameter: 17.8 μm), 30.0 g of crospovidone, 6.0g of anhydrous citric acid and 1.2 g of aspartame, and granulation wascarried out while spraying purified water. After drying, 1.8 g ofmagnesium stearate was incorporated. The resulting powder was tablettedby a pounder (beveled edge, 10 mm in diameter) using a rotary typetabletting machine at the tabletting pressure of 1.0 ton/cm² to providetablets each weighing 300 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 7.1 kg and 20 seconds respectively.

Example 5

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1]was charged with 0.4 g of voglibose, 470.6 g of erythritol [manufacturedby Nikken Chemicals Co., Ltd. (Japan)], 120.0 g of low-substitutedhydroxypropylcellulose LH-33 (content of hydroxypropoxyl group: 5.7% byweight, average particle diameter: 30.8 μm), 6.0 g of anhydrous citricacid and 1.2 g of aspartame, and granulation was carried out whilespraying purified water. After drying, 1.8 g of magnesium stearate wasincorporated. The resulting powders was tabletted by a pounder (bevelededge, 10 mm in diameter) using a rotary type tabletting machine at thetabletting pressure of 1.25 ton/cm² to provide tablets each weighing 300mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 4.5 kg and 23 seconds respectively.

Example 6

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1]was charged with 0.4 g of voglibose, 470.6 g of mannitol [manufacturedby Merck Japan Co., Ltd.], 120.0 g of low-substitutedhydroxypropylcellulose LH-23 (content of hydroxypropoxyl group: 5.7% byweight, average particle diameter: 30.8 [μm), 6.0 g of anhydrous citricacid and 1.2 g of aspartame, and granulation was carried out whilespraying purified water. After drying, 1.8 g of magnesium stearate wasincorporated. The resulting powder was tabletted by a pounder (bevelededge, 10 mm in diameter) using a rotary type tabletting machine at thetabletting pressure of 1.25 ton/cm² to provide tablets each weighing 300mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 4.3 kg and 27 seconds respectively.

Example 7

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1)was charged with 40.0 g of manidipine hydrochloride, 460.94 g oferythritol [manufactured by Nikken Chemicals Co., Ltd. (Japan)], 60.0 gof low-substituted hydroxypropylcellulose LH-33 (content ofhydroxypropoxyl group: 5.8% by weight, average particle diameter: 17.8μm), 30.0 g of crospovidone, 6.0 g of anhydrous citric acid and 1.2 g ofaspartame, and granulation was carried out while spraying purified waterin which was dissolved 0.06 g of yellow iron oxide. After drying, 1.8 gof magnesium stearate was incorporated. The resulting powder wastabletted by a pounder (beveled edge, 10 mm in diameter) using a rotarytype tabletting machine at the tabletting pressure of 1.0 ton/cm² toprovide tablets each weighing 300 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 6.0 kg and 21 seconds respectively.

Test Example 1

Low-substituted hydroxypropylcellulose LH-30 (content of hydroxypropoxylgroup: 14.6% by weight, average particle diameter: 17.26 μm), LH-31(content of hydroxypropoxyl group: 11.0% by weight, average particlediameter: 18.18 alm), LH-32 (content of hydroxypropoxyl group: 8.8% byweight, average particle diameter: 17.57 μm) and LH-33 (content ofhydroxypropoxyl group: 5.8% by weight, average particle diameter: 17.8μm) were administered to 4 females respectively, and dissolubility andtaste were evaluated.

The results are shown in [Table 1]. TABLE 1 Low-substitutedhydroxypropyl- Trial cellulose subject Evaluation LH-30 4/4 difficult ofdissolution in the oral cavity LH-31 4/4 dissolved in the oral cavity,chalky taste LH-32 4/4 dissolved in the oral cavity, chalky taste LH-334/4 dissolved in the oral cavity, no chalky taste

As shown in [Table 1], dissolubility and chalky taste are improved, andfurther no roughness was felt, with respect to the case oflow-substituted hydroxypropylcellulose LH-33 comprising 5.8% by weightof hydroxypropoxyl group.

Test Example 2

Tablets were produced by using low-substituted hydroxypropylcelluloseLH-30 (content of hydroxypropoxyl group: 14.6% by weight, averageparticle diameter: 17.26 μm), LH-31 (content of hydroxypropoxyl group:11.0% by weight, average particle diameter: 18.18 μm), LH-32 (content ofhydroxypropoxyl group: 8.8% by weight, average particle diameter: 17.57μm) and LH-33 (content of hydroxypropoxyl group: 5.8% by weight, averageparticle diameter: 17.8 μm) in accordance with the following manner.

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1]was charged with 398.5 g of erythritol [manufactured by Nikken ChemicalsCo., Ltd. (Japan)] and 100 g of low-substituted hydroxypropylcellulose,and granulation was carried out while spraying purified water. Afterdrying, 1.5 g of magnesium stearate was incorporated. The resultingpowder was tabletted by a pounder (beveled edge, 10 mm in diameter)using a rotary type tabletting machine at the tabletting pressure of 1.0ton/cm² to provide tablets each weighing 300 mg.

The resulting tablets were administered to 4 females respectively, anddissolubility and taste was evaluated.

The results are shown in [Table 2]. TABLE 2 Low-substitutedhydroxypropyl- Trial cellulose subject Evaluation LH-30 4/4 notdissolved in the oral cavity LH-31 4/4 not dissolved in the oral cavityLH-32 4/4 felt adhesiveness in the oral cavity, still chalky taste afterdissolution LH-33 4/4 rapidly dissolved in the oral cavity, a littlechalky taste

As shown in [Table 2], dissolubility and chalky taste are improved, andfurther no roughness was felt, with respect to the case oflow-substituted hydroxypropylcellulose LH-33 comprising 5.8% by weightof hydroxypropoxyl group.

EFFECTS OF INVENTION

The rapidly disintegrable solid preparation of the present invention isusable for treatment and prevention of various kinds of diseasesespecially as the oral rapidly disintegrable solid preparation, which iscapable of being administered to elders or children without water,because the preparation has superior disintegrability and dissolubility.It is also improved in its disintegrability in the stomach.

And, the rapidly disintegrable solid preparation has superior long-termstability because the preparation has suitable strength.

Further, the rapidly disintegrable solid preparation of the presentinvention is improved in dissolubility and chalky taste, and has noroughness.

1. An orally rapidly disintegrable solid preparation which comprises (i)a pharmacologically active ingredient, (ii) a sugar and (iii) alow-substituted hydroxypropylcellulose having 5% by weight or more toless than 7% by weight of hydroxypropoxyl group, wherein said solidpreparation is bucally dissolved in from about 5 to about 50 seconds. 2.(canceled)
 3. A preparation of claim 1, which is a tablet.
 4. Apreparation of claim 1, wherein the sugar is a sugar alcohol.
 5. Apreparation of claim 4, wherein the sugar alcohol is mannitol orerythritol.
 6. A preparation of claim 1, wherein the sugar is in anamount of 5 to 97 parts by weight per 100 parts by weight of the solidpreparation.
 7. A preparation of claim 1, wherein the low-substitutedhydroxypropylcellulose having 5% by weight or more to less than 7% byweight of hydroxypropoxyl group is used in an amount of 3 to 50 parts byweight per 100 parts by weight of the solid preparation.
 8. (canceled)9. A preparation of claim 1, wherein the pharmacologically activeingredient is voglibose.
 10. (canceled)
 11. (canceled)
 12. A preparationof claim 1, wherein the pharmacologically active ingredient iscandesartan cilexetil.
 13. A preparation of claim 3 which comprises finegranules.
 14. A preparation of claim 13, wherein the pharmacologicallyactive ingredient is comprised in fine granules of the solidpreparation.
 15. A preparation of claim 14, wherein (i) a sugar and (ii)a low-substituted hydroxypropylcellulose having 5% by weight or more toless than 7% by weight of hydroxypropoxyl group are comprised in thesolid preparation separately from fine granules.
 16. A preparation ofclaim 15, wherein the sugar is in an amount of 5 to 97 parts by weightper 100 parts by weight of the rest of the solid preparation other thanthe fine granules.
 17. A preparation of the claim 15, wherein thelow-substituted hydroxypropylcellulose having 5% by weight or more toless than 7% by weight of hydroxypropoxyl group is in an amount of 3 to50 parts by weight per 100 parts by weight of the rest of the solidpreparation other than the fine granules.
 18. (canceled)
 19. (canceled)